Basic patent WO 2003029232 describes preparation of vortioxetine of formula I using a reaction in solid phase, wherein piperazine bound to the solid phase reacts with eta(6)-1,2-dichlorobenzene-eta(5)-cyclopentadienyl iron hexafluorophosphate in the presence of potash (K2CO3) in THF with formation of N,N′-disubstituted piperazine of formula II. This substance is then condensed with the sodium salt of 2,4-dimethylthiophenol of formula III, prepared in situ from the respective thiophenol and NaH. This condensation is carried out photochemically; subsequent cleaving from the solid phase by means of trifluoroacetic acid releases vortioxetine. Total yield of the described reaction is 17% (Scheme 1), purity (UV, ELSD) 95%, 100%.

Patent WO 2007/144005 describes a strategy starting from 2-bromoiodobenzene of formula IV and 2,4-dimethylthiophenol of formula III, which, in the presence of suitable catalysts, provide 1-(2-bromophenylsulphanyl)-2,4-dimethylbenzene of formula V. This can also be prepared by coupling of 1-iodo-2,4-dimethylbenzene of formula Via or 1-bromo-2,4-dimethylbenzene of formula VIb with 2-bromobenzenethiol of formula VII. Arylbromide of formula V is then converted to the vortioxetine base of formula I by the reaction with piperazine in the presence of a suitable catalytic system, typically in the presence of Pd(dba)2, BINAP, and t-BuONa. Piperazine can also be replaced by N-Boc-piperazine, providing the intermediate of formula VII, deprotection of which affords vortioxetine of formula I (Scheme 2).

Patent WO 2007/144005 also describes the synthesis of the intermediate of formula VII shown in Scheme 3, consisting in the reaction of 2-bromoiodobenzene of formula IV with N-Boc-piperazine in the presence of a suitable catalytic system, providing an intermediate of formula VIII, further coupling of which with the thiol of formula III provides the intermediate of formula VII.

The present invention, relating to a new procedure of preparing vortioxetine of formula I, in comparison with the known state of the art, provides an advantage of preparing vortioxetine of high purity (99.8%) using, in addition, cheap starting substances. Therefore, the proposed procedure is also beneficial from the economical point of view for industrial use and can be simply reproduced.